Towards a proteome-scale map of the human protein-protein interaction network

Systematic mapping of protein-protein interactions, or 'interactome' mapping, was initiated in model organisms, starting with defined biological processes and then expanding to the scale of the proteome. Although far from complete, such maps have revealed global topological and dynamic features of interactome networks that relate to known biological properties, suggesting that a human interactome map will provide insight into development and disease mechanisms at a systems level. Here we describe an initial version of a proteome-scale map of human binary protein-protein interactions. Using a stringent, high-throughput yeast two-hybrid system, we tested pairwise interactions among the products of approximately 8,100 currently available Gateway-cloned open reading frames and detected approximately 2,800 interactions. This data set, called CCSB-HI1, has a verification rate of approximately 78% as revealed by an independent co-affinity purification assay, and correlates significantly with other biological attributes. The CCSB-HI1 data set increases by approximately 70% the set of available binary interactions within the tested space and reveals more than 300 new connections to over 100 disease-associated proteins. This work represents an important step towards a systematic and comprehensive human interactome project.     

Novel chimaeric protein expressed in Philadelphia positive acute lymphoblastic leukaemia

Cytogenic changes are becoming increasingly important in understanding the pathogenesis of human malignancies. The t(9;22) (q34;q11) translocation is one of the most consistent and generates the Philadelphia chromosome (Ph1) (ref. 1) in chronic myeloid leukaemia (CML); it has also been observed in some acute lymphoblastic leukaemias (ALL) (ref. 2). In CML the breakpoints occur on chromosome 22 in the region designated bcr (ref. 3) and result in the expression of a bcr-abl fusion product of relative molecular mass (MT) 210,000 (210K) with associated in vitro tyrosine kinase activity (P210bcr-abl). In some cases of Ph1-positive ALL, a novel abl-related protein (P190all-abl) of 190K has been shown to have tyrosine kinase activity. In this report we demonstrate that the P190all-abl protein has a bcr determinant from the amino-terminal region, but is lacking a bcr determinant normally found in the P210bcr-abl near the bcr-abl junction. The chimaeric nature of the P190all-abl was confirmed by sequential immunoprecipitation with antisera against abl and bcr peptides.     

Functional similarities in the mechanical design of the aorta in lower vertebrates and mammals

The mechanical properties of the aorta from the toad Bufo marinus, the lizard Gekko gecko and the garter snake Thamnophis radix were compared to those of the rat, by inflation of vessel segments in vitro. The arteries of the lower vertebrates, like those of mammals, were compliant, highly resilient, and non-linearly elastic. The elastic modulus of the artery wall was similar in the lower vertebrates and mammals, at their respective mean physiological pressures. We conclude that the aorta in each of these animals is suitably designed to function effectively as an elastic pulse smoothing component in the circulation; differences in the pressure wave transmission characteristics of lower vertebrates and mammals do not result from dissimilarities in arterial elastic properties, but from substantial differences in heart rate of these two groups.     

Long gamma-ray bursts and core-collapse supernovae have different environments

When massive stars exhaust their fuel, they collapse and often produce the extraordinarily bright explosions known as core-collapse supernovae. On occasion, this stellar collapse also powers an even more brilliant relativistic explosion known as a long-duration gamma-ray burst. One would then expect that these long gamma-ray bursts and core-collapse supernovae should be found in similar galactic environments. Here we show that this expectation is wrong. We find that the gamma-ray bursts are far more concentrated in the very brightest regions of their host galaxies than are the core-collapse supernovae. Furthermore, the host galaxies of the long gamma-ray bursts are significantly fainter and more irregular than the hosts of the core-collapse supernovae. Together these results suggest that long-duration gamma-ray bursts are associated with the most extremely massive stars and may be restricted to galaxies of limited chemical evolution. Our results directly imply that long gamma-ray bursts are relatively rare in galaxies such as our own Milky Way.     

Deletion of Huntington's disease-linked G8 (D4S10) locus in Wolf-Hirschhorn syndrome

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by progressive involuntary movements and dementia. The symptoms of the disease, although devastating in severity, do not usually appear until the third to fourth decade of life. The gene defect is highly penetrant, and results in the loss of neurones in the basal ganglia, globus pallidus, and more diffusely in the cortex. A DNA marker, G8 (or D4S10), is tightly linked to Huntington's disease and this gene has been localized to chromosome 4 (ref. 3). The discovery of this linkage marker raises the possibility of developing a presymptomatic test for the disorder, and of eventually isolating the disease gene based on its map position. We have now regionally localized the DNA marker G8 to the terminal band of the short arm of the chromosome, a region representing approximately 0.5% of the total human genome. The assignment was made by examining DNA from patients with Wolf-Hirschhorn syndrome, a birth defect resulting from partial heterozygous deletion of the short arm of chromosome 4.     

Value of curiosity-oriented research

Is the most profit to be had from research inspired by curiosity or by foresight of practical applications? A recent suggestion that the answer could be found by evaluating curiosity-oriented projects has proved hard to follow up.     

Conformational change and protein-protein interactions of the fusion protein of Semliki Forest virus

Fusion of biological membranes is mediated by specific lipid-interacting proteins that induce the formation and expansion of an initial fusion pore. Here we report the crystal structure of the ectodomain of the Semliki Forest virus fusion glycoprotein E1 in its low-pH-induced trimeric form. E1 adopts a folded-back conformation that, in the final post-fusion form of the full-length protein, would bring the fusion peptide loop and the transmembrane anchor to the same end of a stable protein rod. The observed conformation of the fusion peptide loop is compatible with interactions only with the outer leaflet of the lipid bilayer. Crystal contacts between fusion peptide loops of adjacent E1 trimers, together with electron microscopy observations, suggest that in an early step of membrane fusion, an intermediate assembly of five trimers creates two opposing nipple-like deformations in the viral and target membranes, leading to formation of the fusion pore.